Studies identify vaginal microbiome signatures that could help assess risk of premature birth

vcu healthTwo new studies led by researchers at Virginia Commonwealth University provide a comprehensive profile of the vaginal microbiomes associated with term pregnancy and premature pregnancy — groundbreaking research that may help assess the risk of premature birth, particularly among African American women.

In a study titled “The vaginal microbiome and preterm birth,” scientists conducted one of the largest and most comprehensive longitudinal and multi-omic studies of the vaginal microbiome during pregnancy in the Multi-Omic Microbiome Study: Pregnancy Initiative (MOMS-PI). The researchers demonstrated that using only abundance levels of select vaginal bacterial species, a woman’s risk for preterm birth could be predicted with similar accuracy and specificity as with leading clinical markers.

In an accompanying paper, “Racioethnic diversity in the dynamics of the vaginal microbiome during pregnancy,” the researchers found that African American women who delivered at term had more pronounced changes in vaginal microbiome composition over the course of pregnancy compared to women who did not report African ancestry. In the United States, African American woman are approximately 50% more likely to experience preterm birth than white women.

“We hope to be able to use this microbiome data, coupled with clinical and other observations, to develop a predictive model for preterm birth that will allow us to more accurately identify women with higher risk early in pregnancy,” said Gregory A. Buck, Ph.D., professor in the Department of Microbiology and Immunology and Computer Science at VCU, co-director of the Center for Microbiome Engineering and Data Analysis at VCU, corresponding author on both studies, and principal investigator of MOMS-PI.

Women who delivered preterm exhibited significantly lower vaginal levels of the microbiota species Lactobacillus crispatus and higher levels of BVAB1, Sneathia amnii, TM7-H1, a group of Prevotella species, and several additional bacterial taxa, the study found. Significantly, these microbial signatures were best identified early in pregnancy, before the middle of the second trimester.

“Testing the vaginal microbiome early in pregnancy to assess risk for preterm birth and other pregnancy complications may ultimately help to reduce preterm birth rates and the global health disparities in preterm birth,” said Jennifer M. Fettweis, Ph.D., assistant professor in the Department of Microbiology and Immunology and the Department of Obstetrics and Gynecology, lead author and project director of the MOMS-PI study. Fettweis also coordinated the large interdisciplinary team of more than 50 investigators at VCU as well as collaborating teams from the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS) in Seattle.

Preterm birth affects one of every 10 births in the United States. An estimated 15 million preterm births at less than 37 weeks of gestation occur annually worldwide, and preterm birth remains the second most common cause of neonatal death across the globe and the most common cause of infant mortality in middle- and high-income economies.

“Armed with this knowledge, we are positioned to develop tests that can predict risk of preterm birth, and evaluate interventions to correct the abnormal reproductive tract microbiome that will hopefully avert a preterm delivery,” said co-author Jerome F. Strauss, M.D., Ph.D., professor of obstetrics and gynecology, human and molecular genetics, biochemistry and molecular biology, and physiology and biophysics at the VCU School of Medicine, and principal investigator of the MOMS-PI study.

In the United States, African American women disproportionately bear the burden of risk of preterm birth. In 2016, the rate of preterm birth among African-American women (14%) was about 50% higher than the rate of preterm birth among white women (9%), according to the Centers for Disease Control and Prevention.

“Environmental factors have long been thought to play a major role in preterm birth and population disparities in preterm birth rates. The microbiome of the female reproductive tract has recently become recognized as one of the key environmental factors leading to adverse pregnancy outcomes,” said co-author Kimberly K. Jefferson, Ph.D., associate professor in the Department of Microbiology and Immunology, and principal investigator of the MOMS-PI study.

The manuscript is featured as part of a collection of manuscripts from the National Institutes of Health’s integrative Human Microbiome Project, in which researchers investigated how the microbiome interacts with the host over time in adverse health conditions. All three projects generated large omics datasets that are publicly available for others to mine and use for development of new methods.

Through the HMP projects at VCU, the researchers collected more than a quarter million samples from women at VCU and affiliated Richmond-area sites and through GAPPS collection sites in Washington state who were enrolled through the studies in the Research Alliance for Microbiome Science Registry, or RAMS Registry, which is part of the Vaginal Microbiome Consortium at VCU and that works to foster collaboration among researchers to accelerate knowledge and advance science by facilitating sharing, reuse and linking of data and samples.

The MOMS-PI study investigators generated omics data from more than 12,000 samples, which is linked to rich clinical phenotypes; the omics data is publicly available through the HMP Data Coordination Center.

“This work is only made possible by the recent dramatic advances in high-throughput omic technologies, genomics, metagenomics, metatranscriptomics, immunoproteomic, bioinformatics and computational biology,” said Myrna G. Serrano, Ph.D., associate professor of microbiology and immunology and assistant director of the VCU Genomics Core and lead author of the accompanying manuscript.

The studies, which will be published tomorrow in the journal Nature Medicine, were conducted under the umbrella of multiple awards totaling more than $20 million to the VCU team from the NIH Human Microbiome Project, which over the last decade has explored the connections of host-microbial interactions to health outcomes.

Also publishing today, in the journal Nature, Fettweis, Buck and Strauss co-authored a perspective piece with the integrative HMP (iHMP) Research Network Consortium — which includes NIH, VCU, Harvard University, Stanford University, the University of Maryland and The Jackson Laboratory.

The article focuses particularly on the HMP’s second phase, called the Integrative Human Microbiome Project, which applied multi-omic strategies to explore the dynamic changes in the microbiome and host in pregnancy and preterm birth, inflammatory bowel diseases, and stressors affecting prediabetes.

“Human-associated microbiology now clearly extends beyond infectious and gastrointestinal disease to areas barely imaginable a few decades ago, including metabolism, neoplasia, maternal and child health, and central nervous system function,” the researchers wrote. “As the NIH HMP comes to closure, it is clear that its results have revealed a multitude of new avenues of research and technologies for future investigation, and we look forward to new discoveries based on resources from the program and exciting findings yet to come.”

VCU President Michael Rao, Ph.D., said the university’s research into the microbiome and pregnancy underscores the importance of community engagement in VCU’s basic and clinical research.

“We thank the more than 6,000 women from the Richmond area who participated in these NIH Human Microbiome Project studies, along with clinicians and nurses who assisted in collecting samples in our effort to understand how the microbiome impacts pregnancy,” Rao said. “This is part of our mission: to strive to promote research that improves human health and seeks to address disparities in the health of our community.”

“This transdisciplinary research is foundational and a more in-depth understanding of the microbiome across diverse populations will lead to better pregnancy outcomes in women and ultimately the health of women and infants,” said Srirama Rao, Ph.D., vice president for research and innovation at VCU.

A third and related study into bacteria of the vaginal microbiome will be published in the Journal of Perinatology and was led by researchers at the Medical University of South Carolina and VCU. It found that pregnant African American women who are low in vitamin D have higher levels of bacteria linked to preterm birth.

The VCU studies involved researchers from the VCU School of Medicine, the Center for Microbiome Engineering and Data Analysis, the School of Business, the College of Humanities and Sciences, VCU Life Sciences, the College of Engineering, Children’s Hospital of Richmond at VCU, as well as Emory University, the University of Texas at Austin, West Virginia University, the University of Montana, Pacific Biosciences, the Global Alliance to Prevent Prematurity and Stillbirth, and the University of Washington.

It was supported by a number of NIH grants, including UH3AI083263, U54HD080784, 1R01HD092415, R25GM090084, and R21HD092965, and BMGF PPB from GAPPS. Buck (contact PI/PD), Strauss (PI/PD) Jefferson (PI/PD) and Fettweis (project director) served as the executive committee for the MOMS-PI project; Fettweis serves as the director of the RAMS Registry. Buck co-directs with Krzysztof Cios, Ph.D., chair of the Department of Computer Science in the College of Engineering, the Center for Microbiome Engineering and Data Analysis, which was established to respond to the growing appreciation of the important of the microbiome to human health.

The Vaginal Microbiome Consortium at VCU thanked its partners GAPPS and the Medical University of South Carolina, as well as the NIH Common Fund, the National Center for Complementary and Integrative Health, the Office of Research on Women’s Health, the Eunice Kennedy Shriver National Institute for Child Health and Human Health Development, the National Institute of Allergy and Infectious Diseases, and The Bill and Melinda Gates Foundation.



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